This invention relates to an antithrombogenic-containing polymeric material and process for making the same. More particularly, the invention relates to a method for preparing antithrombogenic polymeric articles which employ covalently bonded hydrophobic groups bonded to the polymeric surface to provide increased antithrombgenic activity.
Extensive investigations have been undertaken over many years to find materials that will be biologically and chemically stable towards body fluids. This area of research has become increasingly important with the development of various objects and articles which can be in contact with blood, such as artificial organs, vascular grafts, probes, cannulas, catheters, hyperalimentation catheters and other long indwelling vascular catheters and the like.
Artificial materials are being increasingly used as blood contact devices and may be subject to potential generation of thrombus. When blood contacts foreign materials a complex series of events occur. These involve protein deposition, cellular adhesion and aggregation, and activation of blood coagulation schemes. Considerable research effort has been focused on this blood-material-interaction in the last twenty years with such devices. The overall objective of these investigations has been to minimize the potential for thrombus formation, such as the device when introduced into the body upon contact with blood.
Various methods have been devised for producing such a material, most of which involve chemically bonding a quaternary ammonium salt to the polymer and then heparinizing the same. Usually, this is done by incorporating an amine in the polymer, quaternizing the amine, and then heparinizing or bonding an antibiotic to the quarernized material.
In one method taught by R. I. Leininger and G. A. Grode, U.S. Pat. No. 3,457,098, a quaternary amine is incorporated into an epoxy resin. Subsequent exposure to sodium heparinate dissolved in water then results in ionically bound heparin. The polymer systems are essentially epoxy resins which are rigid polymers which are not suitable for forming medical devices such as catheters or other devices requiring extrusion. These polymers also are not appropriate where flexibility in the device ls required.
R. I. Leininger and R. D. Falb disclose in U.S. Pat. No. 3,617,344 another process for binding heparin. This system differs from the previous system in that low molecular weight chloromethyl groups are absorbed to the surface of a polymer substrate. Subsequent amination by a tertiary amine and quaternization resulted in a positively charged surface for binding with heparin. The concept, in general, embodies the use of low molecular weight quaternized groups to ionically bind heparin.
U.S. Pat. No. 3,846,353 to H. M. Grotta involves use of long chain alkyl quaternary amines on the surface of a polymer wherein the positively charged surface is exposed to a solution of sodium heparinate. The amines are dissolved in an organic solvent consisting of toluene, petroleum ether and mixtures thereof. One primary deficiency of the Grotta method is the use of toluene as a coating solvent. Toluene, when used with latex materials, results in a swelling of the products and destruction of essential elastic properties, rendering itself practically useless. In particular, this effect is seen with balloons present on balloon catheters wherein the balloon component becomes extremely fragile and is basically destroyed. Residues of toluene that may remain on the devices from processing which are targeted for internal use are thus harmful to the ultimate user. A second deficiency of ionically bonded systems is the short lifetime of the ionically bonded heparin due to desorption.
S. Yen and A. Rembaum prepared a neutral polyurethane elastomer which is subsequently quaternized and ionically bonded to heparin, U.S. Pat. No. 3,853,804. The main disadvantage of this system is that it is a chemical complex and toxic solvents are used to achieve solubility when coating. The coating technique, however, is difficult to perform due to the solvent (DMF) requirement. The patent of N. Harumiya et al., U.S. Pat. No. 3,844,989, describes a polymer composition of water-insoluble cationic copolymers having hydrophilic components, quaternary amine groups, and hydrophobic moieties. Heparin is bonded ionically to the quaternary ammonium groups via absorption after the polymer components are contacted with a heparin solution. This method involves use of complex synthesis procedures and is not readily applicable to coating other polymeric or non-polymeric materials.
U.S. Pat. No. 4,521,564 to Solomon et al. discloses antithrombogenic polyurethane polymers having the antithrombogenic material covalently bound to the polyurethane. The polyurethane polymer material is treated with a solution of a polymeric amine selected from the group consisting of a polyvinyl amine. a polyalkylenimine having 2 to 4 carbon atoms per amine unit and mixtures thereof so that the polymeric amine becomes covalently bonded to the polyurethane substrate. An antithrombogenic agent is then covalently bonded to the polymeric amine.
It would be desirable to provide a material which has excellent biological and chemical stability towards body fluids, namely blood, and which retains its antithrombogenic agent and antibiotic effect for a long term while being slowly leachable when in contact with blood. lt would also be desirable to provide materials which have enhanced antithrombogenic activity.
The present invention accomplishes all of these needs and improves on the prior art compositions and methods of enhancing the availability of the antithrombogenic agent to blood, thereby increasing the agent's activity. Consequently, enhanced hemocompatibility of the products of this invention is also achieved. More particularly, the present invention concerns articles having antithrombogenic properties comprising:
(a) a polymeric solid support structure
(b) a polymeric material rich in amine content which serves as a substrate for an antithrombogenic agent, said polymeric material being selected from the group consisting of primary amines having a carbon chain length of from 2 to 10,000, a polyalkylenimine having 2 to 4 carbon atoms per amine unit and mixtures thereof bonded to said polymeric support structure; and
(c) an antithrombogenic agent covalently bonded to said polymeric material rich in amine content: wherein the activity of the antithrombogenic agent is enhanced by the hydrophobic material or functional groups covalently bonded to the substrate surface.
Those polymeric materials rich in amine content which serve as a substrate. e.g., bonding site, for the antithrombogenic agent, are preferably amine rich polyurethane urea polymers (referred to herein as APU polymers). These polymers are prepared as solutions which are then used to coat the polymeric support structure. For example. if the support structure is a cathether, tubing or other device, it can be dipped, brushed, sprayed or otherwise coated with the amine rich material. The coating bonds to the support structure surface, providing a site on which antithrombogenic materials can subsequently be attached covalently. However, unlike the prior art, the instant invention further prepares the amine rich substrate surface prior to bonding the antithrombogenic agent to the amine substrate. This further treatment comprises the introduction of hydrophobic materials or groups onto the substrate surface.
Preferred polymeric material rich in amine content include polyether based urethaneureas such an poly(ethylene oxide) urethane-urea, poly(propylene oxide) urethaneurea, poly(tetramethylene oxide) urethaneurea; polyester based urethaneureas such as poly(ethylene adipate) urethaneurea, poly(propylene adipate) urethaneurea, poly(tetramethylene adipate) urethaneurea, poly(hexamethylene adipate) urethane urea; other types of polyurethane ureas such as polycaprolactone urethaneurea and polybutadiene urethaneurea. Mixtures of these are also useful.
While the present invention has been described in terms of using the preferred amine rich polyurethane urea polymers as the substrate on which to attach the anlithrombogenio agent, it should be recognized that other substrate materials having active amine groups or groups such as polyamides, polyimides, polyalkylenimines, and polyvinyl amines may be used.
The enhanced antithrombogenic activity of the articles is believed to be due to the greater hydrophobic character imparted to the substrate surface. This effect is achieved by covalently bonding to the substrate surface a moiety selected from the group consisting of a flourine compound, a siloxane compound, a silazane compound, a silane compound, and mixtures thereof. In the case of the fluorine-containing compouds, the fluorine group is believed to covalently bond to the substrate surface. In the case of the siloxane, silane and silazane compounds, the silicone group is believed to covalently bond to the substrate surface.
Useful flourine-containing compounds include Freon.RTM. compounds such as dichlorodifluoromethane, chlorotrifluoromethane, bromotrifluoromethane, tetrafluoromethane, chlorodifluoromethane, fluoroform, 1,1,2-trichlorotrifluoroethane, 1,2-dichlorotetrafluoroerhane, hexafluoroethane, tetrafluoroethylene, as well as hexafluoropropylene, boron trifluoride, silicon tetrafluoride., sulfur hexafluoride, sulfur tetrafluoride, tungsten hexafluoride, and fluorine among others. The preferred fluorinated compound is, however, hexafluoropropylene. Mixtures of these compounds are contemplated.
Those siloxane compounds useful have the formula: ##STR1## wherein R.sub.1, R.sub.2 and R.sub.3 are aliphatic or substituted aliphatic groups having an aliphatic carbon chain of 1-4 carbons; and n is an integer from 1 to 100, preferably from 3 to 20. Thus, aliphatic chains of up to 4 carbons having a benzene ring or other aromatic or aliphatic group substitution thereon are contemplated.
Those silazanes useful include compounds corresponding to the formula: ##STR2## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 can be alkyl C.sub.1 -4 or hydrogen.
Those silane compounds useful have the formula: ##STR3## wherein, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are selected from the group consisting of aliphatic groups, substituted aliphatic groups, aromatic groups, substituted aromatic groups, halogens, alkoxyl groups, vinyl groups and mixtures thereof.
The bonding of the fluorine, siloxane, silane and/or silazane moieties to the polymeric substrate surface is accomplished via glow discharge (ionized gas) treatment. This process is generally referred to in the art as plasma treatment. Plasma treatment is accomplished using a glow discharge ionization chamber, whereby samples are placed in the chamber and the chamber pressure is reduced to a minimal level. e.g., 0.1 torr or less, via a vacuum pump. The fluorine, siloxane, silane and/or silazane compounds are introduced in gaseous form into the plasma chamber to a desired level, e.g., about 0.3 torr, and purged to a level of about 0.1 torr to minimize potential contamination from other gases such as air. Purging is then repeated, and the final desired pressure of the gas is reached. For example, a pressure of about 0.1 to about 5 torrs is desired, and most preferably about 0.3 torrs. Radio frequency power is then generated and applied to the gas in the chamber for a fixed period of time. For example. about 10 to about 100 watts might be applied for a period of about 10 to about 20 minutes. The ionization reaction is allowed to proceed during this interval, at which time the power and vacuum are terminated and air or nitrogen gas is introduced to open the chamber.
It is necessary to maintain a balance of four factors during the plasma treatment of the substrate surface: power (wattage); exposure time (reaction time); gas flow rate; and chamber pressure. If too much wattage is applied for too long a period of time, the polymeric amine compound which serves as the site for bonding the antithrombogenic agent, could lose its functionality through cleavage or substitution by the gaseous moieties in the ionization chamber. Too little wattage and/or exposure produce insufficient bonding of the hydrophobic moieties to the substrate surface. Thus, the wattage (power applied), exposure time of the substrate surface to the gaseous chamber, flow rate of the gas, as well as the chamber pressure, must be controlled within specified ranges. Variation of one of these factors may cause adjustment of the other factors in order to produce the desired result. The wattage applied should be from about 1 to 700 watts, preferably less than about 200 watts and most preferably from about 5 to about 50 watts. The flow rate of the gas in the chamber should be about 1 to about 500 standard cubic centimeters per minute (cc/min), preferably about 1 to about 100 cc/min, and most preferably about 1 to about 50 cc/min. The chamber pressure, during the treatment of the substrate surface, should be maintained in the range of about 0.1 to about 100 torrs (mm of mercury), preferably about 0.2 to about 10 torrs and most preferably about 0.3 to about 5 torrs. Exposure time of the substrate surface to the chamber atmosphere under the above ranges vary widely from a few minutes or hours to about 24 hours. Preferably, at 50 watts, 0.3 torrs and 5 cc/min, a time of about 10 minutes to 1 hour is sufficient to impart excellent hydrophobic character to the substrate surface.